Recent investigations in cell culture systems have resulted in a tentative hypothesis regarding the mechanism of neoplastic transformation at the cellular level. The hypothesis is that the cancer cell is basically characterized by an altered surface membrane which is coupled to a correlative loss of control of cellular multiplication. The overall objective of the present proposal is to determine the discrete steps in the process of malignant transformation by employing the DNA tumor viruses SV40 and polyoma. These viruses program transformation in an orderly fashion. It has been shown that the stable integration of the viral genome provides genetic continuity for the expression of viral genes serving to modify the surface membrane and the control of growth. The present investigation will center around the temporal and physiological relationships between the expression of viral genes, cell surface modifications, and unrestricted DNA synthesis. A variety of virus-cell complexes will be compared, including the lytic, abortive and transformed interactions. The activities of conditional viral mutants will also be analyzed. These studies will include (i) a detailed analysis of glycolipid, glycoprotein and architectural changes in the cellular and nuclear membranes, (ii) an investigation of the structure and composition of interphase chromosomes as an approach to the study of viral and cellular gene transcription and cell DNA replication, and (iii) continued studies on the changes in protein metabolism which result from viral gene activity.